Chemistry Reference
In-Depth Information
FIGURE 21.8
Furin activity and the fate of A
b
PP cleavage by
a
- and
b
-secretases. Low cellular iron levels are thought to increase furin
activity, stimulating the nonamyloidogenic pathway. In contrast, high cellular iron levels decrease furin activity and may activate the amy-
loidogenic pathway.
(From
Altamura & Muckenthaler, 2009
.
Copyright 2009 with permission from IOS Press.)
furin-adenovirus into Tg2576 mouse brains markedly increased alpha-secretase activity and reduced beta-amyloid
protein (Abeta) production in infected brain regions. Further support for the connection between iron metabolism
and AD comes from the identification of a functional IRE in the 5
0
-UTR of the amyloid precursor protein mRNA
(
Rogers et al., 2002
). As is the case of ferritin, APP levels increase in the presence of iron and decrease upon
addition of an iron chelator in neuroblastoma cells. Increased APP formation in parallel with inhibition of
a
-
secretase activity would favour A
b
deposition.
has a very effective binding domain for copper in its N-terminal domain and can bind copper in nmol
amounts (
Figure 21.9
)
. It is unclear whether APP or A
A
b
, when associated with copper, are in fact neuronal
metallo-chaperones. Knock-out and knock-in mice for APP show that in the former, cerebral cortex copper levels
are increased, whereas in the latter, reduced copper levels were assayed. Copper was also influential in APP
processing in the cell; copper will reduce levels of A
b
b
and cause an increase in the secretion of the APP
ectodomain.
Neurofibrillar tangles, NFTs, contain redox active iron. Accumulation of tau in neurofibrillary tangles is
associated with the induction of haem oxygenase 1, HO-1 a potent antioxidant, which plays an important role in
metabolising haem released from damaged mitochondria. HO-1 will reduce oxidative damage but Fe
2
รพ
will be
released which may participate in Fenton chemistry to produce hydroxyl radicals. Tau within the neurofibrillary
tangles is oxidatively damaged.
It has been suggested that the formation of the
b
-sheet configuration of A
b
may actually be a protective
mechanism, and that the increased synthesis of APP and A
b
is an attempt by the brain cells to detoxify the elevated
